Medicinal feed for the systemic treatment of ectoparasitic and ectobacterial diseases of fish

ABSTRACT

The present invention provides a medicinal feed for fish, which comprises at least one compound selected from the group consisting of thionine, nitrothiazole, nitrofuran, quinoline and acridine derivatives, compounds splitting off aldehydes, transition metal derivatives, metal colloids, hexamethylenetetramine and/or quaternary ammonium salts as active materials.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 08/499,985filed Jul. 10, 1995, pending which is a divisional application of U.S.Ser. No. 08/287,754 filed Aug. 9, 1994, now abandoned which is adivisional application of U.S. Ser. No. 07/949,324 filed Sep. 22, 1992,now U.S. Pat. No 5,618,847, which is a continuation of U.S. Ser. No.07/709,867 filed Jun. 4 1991, now abandoned which claims priority fromGerman application P40 17 964.8 filed Jun. 5, 1990.

BACKGROUND OF THE INVENTION

The present invention is concerned with a medicinal feed for thesystemic treatment of parasites in fish.

The care, breeding, and maintenance of fresh water and marine fish inhobby aquaria, in ponds and, to an even greater extent, in intensivemaintenance installations of fish farming and aquaculture, arethreatened by parasitic diseases which can endanger the fish and resultin considerable financial losses. The following organisms pathologicalto fish occur especially frequently: dinoflagellates: Oodiniumpillularis (fresh water) and Oodinium ocellatum (seawater); flagellates:Costia necatrix and Hexamita symphysodonis; ciliates: Ichthyophthiriusmultifilis (fresh water); monogenes: skin and gill flukes, for exampleGyrodactylus and Dactylogyrus.

The treatment of ectoparasitoses, i.e., of diseases caused by parasiteswhich live in or on the outer skin of fish, today occurs exclusively bythe so-called bath therapy in which antiparasitic material is added tothe maintenance water in appropriate biocidal concentrations.

Frequently, only the free-swimming parasitic stages, the so-calledswarms, are thereby damaged but not the stages sitting securely in theskin or under the outer skin.

Consequently, the total treatment is based on the killing off of theswarms. There is no prevention of a new infection or reinfection or noeffect on the immune system of the fish which additionally orexclusively combats the parasitic pathogenic stages.

According to the prevailing expert opinion, ectoparasitic diseases canonly be treated externally and not by means of systemically administeredcurative agents, for example, medicinal feeds.

Endoparasitic diseases, for example, parasites of the gut, can betreated successfully almost exclusively by systemically administeredcurative agents, for example, medicinal feeds, such as are described inthe literature (see N. Herwig, "Handbook of Drugs and Chemicals used inthe Treatment of Fish Diseases", pp. 128 and 136, pub. Charles C.Thomas, Springfield, Ill., U.S.A.; E. Amlacher, "Taschenbuch derFischkrankheiten", pub. Gustav Fischer Verlag, Stuttgart, 1981; L.Zemer, Das Aquarium, 220, 515/1987).

The bath therapy of ectoparasitic diseases of fish (fancy fish anduseful fish) is frequently carried out with the use of biocidally orantiseptically acting dyestuffs, for example, of the triphenylmethaneand acridine group of derivatives. These compounds include, for example,N- 4-4-(diethylamino)-phenyl!-phenylmethylene!-2,5-cyclohexadien-1-ylidene!-N-ethyl-ethanaminiumsulphate (brilliant green); N- 4-4-(dimethylamino)-phenyl!-phenylmethylene!-2,5-cyclo-hexadien-1-ylidene!-N-methyl-methanaminiumchloride and oxalate (malachite green); N- 4- bis-4-(dimethylamino)-phenyl!-methylene!-2,5-cyclohexadien-1-ylidene!-N-methylmethanaminiumchloride (gentian violet); 3,6-diamino-10-methylacridinium chloridemixed with 3,6-dimainoacridine (acriflavine); 9-aminoacridine; and2-ethoxy-6,9-diaminoacridinium lactate monohydrate (Rivanol).

In addition, active antiparasitic materials from other classes ofchemical compounds are also used, for example, quinoline derivativessuch as quinine; quaternary ammonium salts; silver and copper salts;metal colloids, nitrofurans, for example, nifurpirinol; andnitrothiazoles, for example, 2-amino-5-nitro-thiazole.

However, the bath therapy with these antiparasitic active materialsinvolves several disadvantages. Parasites in or under the outer skin ofthe fish are mostly not affected. Since frequently the whole of themaintenance water (aquarium, pond, or intensive breeding installation)is treated, in addition, a very large use of active material isnecessary.

Furthermore, the active material concentration is very uncertain since,during the treatment, due to decomposition processes (chemical,biological, and photochemical) and adsorption on surfaces, losses ofactive material occur which cannot be previously calculated. Since, to alarge extent, the materials used are dyestuffs, the intensive colorationof the water and the tendency of the bath solution to color variousmaterials is also disturbing. Since the whole of the maintenance systemis therapeutically treated, the presence of the biocidally activematerials leads to undesirable and, under certain circumstances, evenharmful side effects, for example, damage to other important waterorganisms, such as aquatic plants and planktonic organisms and damage ofthe biological flora in filter systems and thus a negative influence onthe biological breakdown capacity. The above-mentioned therapeuticallyactive compounds also have a strong fish toxicity and especially gilltoxicity so that the safety of the treatment is limited.

SUMMARY OF THE INVENTION

The present invention is a medicinal feed for fish containing atriphenylmethane derivative or a combination of triphenylmethanederivatives alone or in combination with one or more compounds selectedfrom thionine, nitrothiazole, nitrofuran, quinoline and acridinederivatives, compounds splitting off aldehydes, transition metalderivatives, metal colloids, hexamethylenetetramine and/or quaternaryammonium salts as active ingredients and a pharmaceutically acceptablecarrier.

The medicinal feed can be an enteral pharmaceutical compositioncontaining an active ingredient in a concentration of from about 0.005to about 10% by weight. Preferably it contains an active ingredient, oringredients, in a concentration of from about 0.05 to about 3% byweight.

The medicinal feed can be a feed mixture.

Preferred active compounds are malachite green, a salt thereof or aderivative thereof; for example, malachite green chloride, malachitegreen carbinol base.

Other preferred active compounds are crystal violet, 9-aminoacridine,ethacridine lactate, acriflavine and methylene blue.

DETAILED DESCRIPTION

The present invention provides for the therapy of ectoparasitic andectobacterial diseases in fish which avoid the above-mentioneddisadvantages.

The present invention is a medicinal feed for fish containing atriphenylmethane derivative or a combination of triphenylmethanederivatives alone or in combination with at least one compound selectedfrom the group comprising thionine, nitrothiazole, nitrofuran, quinolineand acridine derivatives, compounds splitting off aldehydes, transitionmetal derivatives, metal colloids, hexamethylenetetramine and/orquaternary ammonium salts as active materials.

The present invention is also concerned with the use of this medicinalfeed for the systemic treatment of ectoparasitic and ectobacterialdiseases. The medicinal feed according to the present inventionpreferably contains the active material in a concentration of from 0,005to 10% by weight and more preferably of from 0.05 to 3% by weight.

The disadvantages of the bath therapy described above can be completelyavoided by the use of the medicinal feed according to the presentinvention, which is completely surprising to the expert, for thesystemic treatment of ectoparasitic and ectobacterial diseases of fancyand useful fish.

The effectiveness of systemically acting medicinal feeds againstectoparasites and ectobacteria, i.e., organisms which have attacked fishon and/or under the external skin and mucous membrane layer, is novel,surprising and not foreseeable by the expert. In comparison with theknown bath therapy, the novel therapy of the present invention offersconsiderable advantages. Thus, for example, a precise, oraladministration of the medicinal feed to the fish is possible. Parasitesor bacteria in or under the outer skin of fish are, surprisingly,therapeutically attacked. The extraction of the active material from themedicinal feed by the maintenance water is very small. The amount ofactive material administered is very small, so the maintenance systemhas only negligible amounts of the active material. The toxic stressingof other water organisms is reduced practically to zero. The breakdownactivity of the filter is not impaired. Coloration of the water is nolonger recognizable. The gill toxic action is eliminated. Incalculablelosses of active material during the treatment also no longer occurs.

A desired side effect is, at the same time, also the simultaneouscombating of endoparasites possibly present.

The choice of appropriate active materials, with the novel medicinalfeeds can also combat the following ectoparasites in the case of fancyand useful fish: (only the most important causal species are here givenor have already been mentioned hereinbefore) dinoflagellates, such asOodinium; flagellates, such as Costia (Hexamita); ciliates, such asIchthyophthirius, Cryptocarion, Chilodonella and Trichodina; andMonogenea, such as skin and gill flukes, for example, Gyrodactylus andDactylogyrus.

Surprisingly, ectobacterioses, for example, all skin and gill infectionsdue to gram-negative and gram-positive bacteria, for example, Aeromonas,Pseudomonas, and Flexibacter, have also proved to be combatable.

In the systemic treatment of the ectoparasitoses and ectobacterioses,naturally at the same time, all systemic internal diseases of fancy anduseful fish due to parasites and bacteria are treated when the activematerials used have an appropriate spectrum of activity. This is abeneficial side effect.

Surprisingly, active materials which have previously either been usedexclusively for bath therapy or, in exceptional cases, in the form ofenteral pharmaceutical compositions exclusively for the treatment ofinternal parasitoses and preferably of gut parasitoses can be used forthe systemic treatment of ectoparasitoses and ectobacterioses.

Triphenylmethane derivatives, for example, malachite green (as salts,for example chloride, oxalate and sulphate), malachite green carbinolbase, brilliant green (all salts), crystal violet (all salts), gentianviolet (all salts), pararosaniline (all salts, base), fuchsine(rosaniline) (all salts) as well as all leuco compounds of the cationsof the dyes have been used exclusively for bath therapy. In addition,thionine derivatives, with the exception of methylene blue B; additionalthionine derivatives with lower N-methylated derivatives as well as allleuco compounds of thionine derivatives; and nitrothiazole derivatives,for example, 2-amino-5-nitrothiazole and transition metal derivatives,for example, copper and silver salts and complexes thereof, copper andsilver metal colloids; and all microbicidal quaternary ammonium saltshave been used.

Quinoline derivatives, for example:

3 -Quinolinecarboxylic acid, 6-(decyloxy)-7-ethoxy-4-hydroxy-, ethylester;

Cinchonan-9-ol, 10,11-dihydro-6'-methoxy-, (8α,9R)-;

3-Quinolinecarboxylic acid, 6,7-bis (cyclopropyl-methoxy)-4-hydroxy-,ethyl ester;

Phenol, 4- (7-chloro-4-quinolinyl) amino!-2,6-bis (hexylamino)methyl!-;

Phenol, 4- (7 -chloro-2-methoxybenzo b!-1,5-naphthyridin-10-yl)amino!-2,6-bis (1-pyrrolidinylmethyl)-;

1,4-Piperazinediethanamine, N,N'-bis(7-chloro-4-quinolinyl)-α,α'-dimethyl-;

Phenol, 4- (7-chloro-4-quinolinyl)amino!-2- (diethylamino) methyl!-;

1,4-Pentanediamine, N4-(7 -chloro-3-methyl-4-quinolinyl )-N1,N1-diethyl-;

1,3-Propanediamine, N,N-diethyl-N'-(6-methoxy-8 -quinolinyl)-;

6-Quinolinol, 8- 3- (dimethylamino)-1-methylpropyl!amino!-;

1,4-Pentanediamine, N4-(6-methoxy-8-quinolinyl)-;

1,4-Pentanediamine, N1-(6-methoxy-8-quinolinyl)-;

1,4-Pentanediamine, N1, N1-diethyl -N4- 6-methoxy-22-(4-nitrophenyl)ethenyl!-4-quinolinyl!-, phosphate (1:3);

1,4-Pentanediamine, N4-(7-chloro-4-quinolinyl)-N1,N1-diethyl-;

4-Quinolinemethanol, α-2-piperidinyl-2,8-bis(trifluoromethyl)-,(R*,S*)-(.±.)-;

1,4-Pentanediamine, N4-(6-methoxy-8-quinolinyl)-; and

Quinolinium, 4-amino-2-methyl-1- 6-(2-methyl-4-quinolinyl)amino!hexyl!-, iodide, monohydrochloride areexpected to be useful in the instant invention.

Moreover, some of the active compounds have been used in the mentionedpharmaceutical compositions for peroral treatment, but in no case forthe treatment of ectoparasitic diseases, because this indication was notknown. Compounds of this type are acridine derivatives, for example,acriflavine, 9-aminoacridine, atebrin, rivanol, and all reducedprecursors of the acridine derivatives; methylene blue B; nitrofuranderivatives, for example, nifurpirinol; quinoline derivatives, forexample, quinine (all salts, bases); aldehydes, for example,formaldehyde and derivatives thereof, for example,hexamethylenetetramine; enheptine and the N-acetyl derivativeacimitrazole as well as trypaflavine and acriflavine.

Useful as a matrix or vehicle for the systemic use of theabove-described anti-ectoparasitic and anti-ectobacterial activematerials are: film-like feed, flock feed, pelletized feed, extrudedfeed, expanded feed, granulated feed, ground feed, pulverised feed,tableted feed, feed pastes and feed suspensions, feed gels and aspicfeed or other carriers well enriched with attractants or baits.

The introduction of a therapeutically active material takes place in atechnically appropriate preliminary stage of the production process, forexample, into the raw material powder mixture and the water-containingprocess stages thereof in such a manner that distribution of the activematerial in a finished powder as fine and homogeneous as possible isachieved.

It has been found that most of the described active materials,especially when present in cationic form (for example, malachite green,acridinium salts, quaternary ammonium salts and the like), are verystrongly adsorptively bound by the carrier or feed materials. The resultof this outstanding active material immobilization is that no leachingout by water takes place and no discoloration, for example, on the handsof the user, results. In this way, a high degree of safety in the use ofactive materials which are toxic or dangerous to humans is achieved;thus no safety measures are necessary in the case of production,packaging, storage and in the case of therapeutic use.

Similar advantages are achieved by using reduced precursors of thecations of the dyes, e.g., leuco compounds, or other derivatives withpoor solubility in water.

The following table summarizes, by way of example, the range ofconcentrations in the feed for some active materials. All the statementsrefer to mg/kg of active material of feed or to weights percent.

    ______________________________________                                                               Preferred                                                         Concentration                                                                             Concentration                                                     Range       Range                                                  Active Material                                                                            mg/kg     %       mg/kg   %                                      ______________________________________                                        Malachite Green                                                                            100-      0.01-   200-    0.02-                                  Chloride (and                                                                              10000     1.0     4000    0.4                                    Other Salts)                                                                  Malachite Green                                                                            100-      0.01-   200-    0.02-                                  Carbinol Base                                                                              10000     1.0     4000    0.4                                    Crystal Violet                                                                             100-      0.01-   200-    0.02-                                  (Gentian     10000     1.0     4000    0.4                                    Violet)                                                                       9-aminoacridine                                                                            100-      0.01-   500-    0.05-                                               50000     5.0     20000   2.0                                    Ethacridine  200-      0.02-   1000-   0.1-                                   Lactate      50000     5.0     30000   3.0                                    (Rivanol)                                                                     Acriflavine  200-      0.02-   500-    0.05-                                  (Trypaflavine)                                                                             50000     5.0     30000   3.0                                    Methylene Blue                                                                             200-      0.02-   500-    0.05-                                               20000     2.0     10000   1.0                                    ______________________________________                                    

The medicinal feed variants of the present invention which can be usedto treat ectoparasitoses and ectobasterioses have a beneficial sideeffect in that systemic diseases due to endoparasites and endobacteriain all types of fish of the fancy and the useful fish groups (freshwater and seawater) in all existing and in the usual closed andnonclosed maintenance systems are also treated.

Even fish in their natural environment can be treated therapeutically bytaking the feed.

A medicinal feed of the present invention is produced in the mannerfamiliar to one skilled in the art in that either the desired activematerial is admixed with the raw feed mixture before the final workingup to give flocks, pellets, tablets, capsules, extrudates or the like inthe necessary amount or the final feed product is sprayed with asolution of the active material and subsequently finally dried.

The following examples are given for the purpose of further explainingthe present invention without limiting the scope of the presentinvention:

EXAMPLE 1

A flock feed for fancy fish is enriched with 0.2% by weight of malachitegreen and given to ectoparasitically diseased fancy fish instead of thenonmedicated flock feed used for normal feeding.

A. Treatment of Ichthyophthirius

30 Giant loach (Botia macracautha) and 30 thread fish (Trichogastertrichopteri) which were severely infected with Ichthyophthirius were fedonce a day with the malachite green-containing medicinal feed. Incomparison with the untreated control, within 5 days a 100% treatmentsuccess was achieved.

B. Treatment of Costia and Chilodonella

40 Red neons (Paracheirodon axelrodi), which were double infected withCostia and Chilodonella, were fed once a day with malachitegreen-containing medicinal feed. In comparison with the untreatedcontrol, within 5 days a 100% treatment success was achieved.

C. Other Ectoparasitic Diseases

Analogous to the above-described Examples, with the described malachitegreen-containing medicinal feed, the following ectoparasitoses could becompletely healed: Oodinium pillulare, Trichodina spec. andGyrodactylus.

Corresponding healing successes are also achieved with the othermedicinal feeds described hereinbefore.

Especially advantageous in the case of the treatment of ectoparasitoseswith the instant medicinal feeds is their complete harmlessness: all thetreated fish showed no signs of indisposition or of damage during andafter the treatment.

Furthermore, the effectiveness of triphenylmethane dyestuffs, forexample, brilliant green and malachite green, against gram-positivebacteria makes these active materials in the form of medicinal feedsaccording to the present invention of possible additional use for thetreatment of external and internal bacterioses with gram-positivepathogens, for example, with Corynebacterium, Nocardia, andMycobacterium.

The known effectiveness of crystal violet and gentian violet againstinternal worm diseases in humans and mammals can also be utilized forcombating external and internal helminthoses in fish. Helminthoses whichare brought about, for example, by Monogenea (for example, Gyrodactylusand Dactylogyrus), Cestoda, Trematoda (for example, Diplostomum) andNematoda (for example, Capillaria) can be treated.

A further therapy lies in the combined use of the medicinal feed of thepresent invention and a healing agent bath in which similar or otherantiparasitic or antibacterial active materials have been added to thewater in a therapeutically effective amount. This combination therapyoffers the possibility also of combating the nonparasitizing,free-swimming or firmly fixed (to plants, stones, or any surfaces)pathological stages. Advantages resulting therefrom are a partial orcomplete disinfection of the system, a reduction of the reinfection rateof the fish by free-swimming pathogenic stages, as well as combating ofparasitizing pathogens on fish internally by the medicinal feed andexternally by the healing bath.

In the case of the additional administration of the active material viathe water, all the initially mentioned disadvantages of a bath therapywill arise.

We claim:
 1. A composition comprising and enteral solid medicinal foodpreparation for fish containing an active compound, a quinolinederivative, in a concentration of 0.005 to 10% by weight wherein theactive compound is very strongly adsorptively bound by carriers and feedmaterials so no leaching out by the water takes place.
 2. A compositioncomprising an enteral solid medicinal food preparation for fishaccording to claim 1, containing an active compound in a concentrationof 0.05 to 3% by weight.
 3. A composition according to claim 1 which isa feed mixture.